Fanconi Anemia, Complementation Group S
A number sign (#) is used with this entry because of evidence that Fanconi anemia complementation group S (FANCS) is caused by compound heterozygous or homozygous mutation in the BRCA1 gene (113705) on chromosome 17q21.
Heterozygous mutation in the BRCA1 gene can also cause susceptibility to familial breast-ovarian cancer-1 (BROVCA1; 604370).
DescriptionFanconi anemia complementation group S is an autosomal recessive disorder characterized by developmental delay apparent from infancy, short stature, microcephaly, and coarse dysmorphic features. Laboratory studies show defective DNA repair and increased chromosomal breakage during stress. Some patients may have radial ray anomalies, anemia, and increased risk of cancer; patients often have a family history of cancer in family members who have heterozygous mutations (summary by Freire et al., 2018).
For additional general information and a discussion of genetic heterogeneity of Fanconi anemia, see 227650.
Clinical FeaturesDomchek et al. (2012) reported a 28-year-old woman with a complex phenotype suggesting Fanconi anemia. The patient presented with stage IV papillary serous ovarian carcinoma at age 28 years. She had a significant medical history of microcephaly, short stature, and developmental delay with limited speech. She had coarse features with low anterior hairline, macrognathia, prominent nasal bridge, and small alae nasi; she did not have obvious abnormalities of the thumb or radial ray. Although she had normal blood count at presentation, she developed significant toxicity and bone marrow failure resulting in death after chemotherapeutic treatment with an interstrand crosslinking agent. The patient had a family history of breast and ovarian cancer in the maternal line and a history of various cancers in the paternal line.
Sawyer et al. (2014) reported a woman, born of unrelated Finnish parents, who presented at birth with microsomia and dysmorphic features, including microcephaly, sparse hair, upslanting palpebral fissures, blepharophimosis, epicanthal folds, hypertelorism, narrow palate with dental malocclusion, and hyper- and hypopigmented skin lesions. She also had short stature, duodenal stenosis, proximally placed thumbs, and hyperextensible knees. She had delayed speech and mild intellectual disability. Additional features included conductive hearing loss and a history of hip dislocation. At age 23 years, she was diagnosed with ductal breast carcinoma. She did not experience unusual treatment-associated toxicity, and she did not have bone marrow failure. Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls, consistent with a diagnosis of Fanconi anemia. There was a strong family history of cancer on both sides, including ovarian, endometrial, and stomach cancer.
Freire et al. (2018) reported a 2.5-year-old girl, born of consanguineous Brazilian parents, with FANCS. She had intrauterine growth retardation, microcephaly (-7.7 SD), short stature (-6.1 SD), failure to thrive, delayed development, and dysmorphic facial features, including thickened earlobes, long eyelashes, microphthalmia, full upper lip, large teeth, anteverted nose, clinodactyly, and hyperchromic spots on the trunk and feet. Her blood counts were normal, and she did not have radial ray abnormalities. Genetic testing for the cause of short stature revealed BRCA1 mutations.
Seo et al. (2018) reported 4 children from 2 unrelated consanguineous families (family A of Arab descent and family B of Turkish descent) who were born with multiple congenital anomalies and severe chromosomal fragility. All 4 children had failure to thrive, microcephaly, global developmental delay with impaired intellectual development, microphthalmia, and skin pigmentation lesions. Two sibs in family A had dysmorphic features, including triangular facies, upslanting palpebral fissures, and micrognathia. The 2 sibs in family B had brain gliosis. One child in family A developed fatal T-cell acute lymphoblastic leukemia at age 5, and 1 child in family B developed a neuroblastoma at age 2. Although chromosome breakage was increased in vitro, none of the patients had anemia or bone marrow failure. The patient with neuroblastoma was able to tolerate chemotherapy, which is unusual for a patient with Fanconi anemia, suggesting some residual BRCA1 function. Both families had a history of cancers, including intestinal, urologic, lung, and esophageal, although none of the 4 parents had cancer.
InheritanceThe transmission pattern of FANCS in the family reported by Freire et al. (2018) was consistent with autosomal recessive inheritance.
Molecular GeneticsIn a 28-year-old woman with a complex phenotype consistent with FANCS, Domchek et al. (2012) identified 2 mutations in the BRCA1 gene (V1736A, 113705.0038 and c.2457delC, 113705.0039), as well as a variant of unknown significance in the BRCA2 gene (c.971G-C, R324T). In vitro functional expression studies showed that the BRCA1 V1736A variant was a hypomorphic allele, with decreased localization to double-strand breaks and decreased interaction with RAP80 (UIMC1; 609433) compared to wildtype. No studies of the BRCA2 variant were performed. The patient's mother died of ovarian cancer at age 55; her DNA was not available. A maternal great-aunt with both breast and ovarian cancer carried a heterozygous V1736A mutation, and another maternal great-aunt with peritoneal cancer carried the V1736A mutation and the BRCA2 R324T variant. A heterozygous V1736A mutation was also found in 2 unaffected family members. Tumor tissue from the patients with a heterozygous V1736A mutation showed loss of heterozygosity for the wildtype BRCA1 allele, suggesting that the V1736A mutation is pathogenic.
Sawyer et al. (2014) reported a woman with FANCS who was compound heterozygous for mutations in the BRCA1 gene (R1699W, 113705.0040 and c.594_597del4, 113705.0041). Patient lymphocytes showed increased chromosomal breakage and radial chromosome formation compared to controls. The patient's mother, who was heterozygous for the 4-bp deletion, had ovarian cancer. There was a strong family history of cancer, including ovarian, endometrial, and stomach cancer. Studies of patient cells showed decreased BRCA1 and RAD51 (179617) foci in response to insult, suggesting impaired double-strand break repair function. Ectopic expression of wildtype BRCA1 restored these repair functions. The R1699W mutation had previously been identified in heterozygous state in a Scandinavian family (LUND279) segregating breast and ovarian cancer by Vallon-Christersson et al. (2001).
In a 2.5-year-old girl, born of consanguineous Brazilian parents, with FANCS, Freire et al. (2018) identified a homozygous nonsense mutation in the BRCA1 gene (C903X; 113705.0042). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was found in heterozygous state in her parents. Patient cells showed increased chromosomal breakage compared to controls. The patient's mother was subsequently screened and found to have breast cancer. There was additional family history of breast cancer on the maternal side.
In 4 patients from 2 unrelated consanguineous Middle Eastern families with a complex phenotype consistent with FANCS, Seo et al. (2018) identified homozygous nonsense mutations in the BRCA1 gene (W372X, 113705.0043 and L431X, 113705.0044). Both mutations, as well as the previously reported C903X mutation (Freire et al., 2018), occurred in exon 11. Complete loss of BRCA1 was thought to be embryonic lethal; however, homozygosity for these nonsense mutations was viable in these patients due to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5-prime to the mutations and produces 2 short isoforms that lack the residues affected by the mutations. Fibroblasts derived from 1 patient showed no detectable full-length BRCA1 protein, but had protein levels corresponding to one of the normal isoforms that retain some capacity to repair DNA damage and can partially compensate for loss of the full-length protein.